In Phase I, quantitative assays were developed to screen for therapeutic agents that block the replication of hepatitis B virus (HBV) in chronically infected cells. The first objective of Phase II studies is to simplify the in vitro testing system, to reduce costs and labor, and to enhance reliability and accuracy. The second objective of Phase II studies is to utilize the improved assays to examine 5 to 10 model compounds that inhibit HBV or other hepadnaviruses in animal models. These studies will compare the anti-HBV activity in the in vitro tissue culture assay to that observed in vivo. In the second year of Phase II, the third objective is to screen at least 100 antiviral compounds in collaborative programs to identify potential technical problems associated with an accelerated testing schedule, demonstrate the validity of the testing procedures to collaborating partners for future Phase III studies, and potentially identify parental compounds which may be modified to improve efficacy. In Phase III, it is anticipated that 300 to 1000 compounds will be tested yearly. The pace of testing will be determined by the success in streaming the Phase II assays and by financial support from collaborative partners.